Circulating FFAs: origins and lipotoxic effects. Circulating FFAs: origins and lipotoxic effects. Systemic FAs are present in three forms: (1) FFAs released from the cells and bound to albumin, (2) exogenous FAs complexed as TAGs in chylomicrons (CMs), and (3) endogenous FAs complexed in TAGs in VLDL. Ingested TAGs are hydrolyzed to FAs and monoacylglycerol by pancreatic enzymes, and these hydrolysis products are solubilized by bile acids or absorption by intestinal enterocytes. The absorbed FAs and monoacylglycerol are re-esterified to TAGs, which are assembled into CMs that are secreted into the lymphatic system and ultimately drain into the systemic circulation via the thoracic duct. Within the liver, synthesized apo (i.e., apoB and apoE), cholesterol esters (CEs), and TAGs are assembled into VLDL particles that are secreted into the plasma. Lipoprotein lipase (LPL), an enzyme present on the endothelial cell surface, hydrolyzes the TAG component of CMs and VLDL, releasing FFAs that bind albumin or are taken up by cells (i.e., muscle and adipose tissue) and resulting in CM remnants and intermediate-density lipoprotein (IDL), respectively. Circulating FFAs gain entrance into tissues via diffusion or specialized plasma membrane fatty acid binding proteins (FABPpm). Once in the cytosol, FAs bind to cellular fatty acid binding proteins (FABPc) and engage in anabolic/synthetic pathways (phospholipid, DAG, and ceramide synthesis), catabolic/oxidation pathways, or are stored as TAGs. Intracellular lipolysis releases FAs from TAGs, which can efflux to the extracellular space via diffusion and bind to serum albumin. Elevated levels of circulating FFAs of any origin are associated with various tissue toxic effects (lipotoxicity), among which renal disease expands the spectrum of cardiometabolic disorders. Mψ, macrophage; SkM, skeletal muscle; Myoc, myocardium; NASH, nonalcoholic steatohepatitis. Mariana Murea et al. CJASN 2010;5:2373-2379 ©2010 by American Society of Nephrology